The present invention generally relates to devices and methods for treatment of cancer and particularly breast cancer and specifically to devices and methods for the regional delivery of multiple cytotoxic agents in a programmable, sequential manner and for the directed assembly of wound repair tissues.
Every adult is at risk for breast cancer. One in nine women who live to the age of 90 will be treated for breast cancer at some time in her life, and more than 180,000 women in the United States were diagnosed with the disease in 2000. Although breast cancer is rare in men, it does occur: an estimated 1,400 cases will be diagnosed in American men in the year 2002. In 1999, approximately 43,000 women died from the disease according to the American Cancer Society. Breast cancer is the most common form of cancer in women and ranks as the second leading cause of cancer deaths among women of all ages. Breast cancer is the number one cause of cancer death for women aged 29-59.
Despite the development of innovative systemic medical therapies for the treatment of breast cancer, local disease control is still a problem. This is also true for other common malignancies such as prostatic carcinoma and colon cancer. Under most current systemic therapy protocols, chemotherapeutic drugs are given to patients systemically as an adjunct to the removal of malignant tumors. Even with preoperative and postoperative radiation therapy, local recurrences often develop. Because of the toxicity of the drugs, the attainable concentration of an active drug in the tumor after systemically-administered chemotherapy is, in part, restricted by the dose-limiting systemic toxicity tolerated by the body. Pre-operative high dose chemotherapy or radiation therapy can adversely affect normal tissue healing, add morbidity and expense and may allow primary tumors that are insensitive to preoperative treatment an opportunity to extend locally, to distant sites, or both.
Breast cancer can be detected at an early treatable stage. Five year survival after treatment for early-stage breast cancer is 97%. The basis for contemporary breast cancer treatment dates back to the 1890s when William Halsted developed the radical mastectomy; a technique for removing a breast, the underlying chest muscle and the lymph nodes in the armpit. According to Halsted, breast cancer could be cured by carving a wide clearance around the initial tumor and its draining sites leaving clear margins of healthy tissue. Today, a modified radical mastectomy with preservation of the pectoral muscles, a somewhat less severe version of the Halsted operation, is still used in approximately 66% of breast cancer surgeries.
While modified radical mastectomy remains the dominant form of treatment for early cancer of the breast, a much less drastic operation called a lumpectomy (sometimes also called breast conserving therapy) combined with radiation therapy has recently been adopted and is used in a third of tumor removal surgeries. As the name suggests, a lumpectomy procedure involves only the removal of the tumor along with a “shell” of healthy tissue to ensure that the whole tumor is taken. There is clear evidence that a lumpectomy, when followed by radiation therapy, is just as effective as the modified radical mastectomy in most situations. According to the New England Journal of Medicine, radiation following lumpectomy resulted in a five-year survival rate of 85 percent, as compared with 76 percent with total mastectomy. At eight years, 90 percent remained free of ipsilateral breast tumor as compared to 61 percent of those not treated with irradiation after lumpectomy. Radiation, however, has no known effect on distant metastases which are the chief sources of danger.
Any improvement in the treatment of breast cancer will probably come from chemotherapy. Used as an adjuvant therapy to surgery, chemotherapeutic compounds kill cancer cells including any metastases lurking in the body. Because of the side effects of the agents, chemotherapy, until recently, was a treatment of last resort, administered only to patients with extensive metastatic disease. Even today, despite discoveries that moderate side effects, chemotherapy is not easy for the patient. Chemotherapy for breast cancer is usually given in the form of a multi-drug regimen, one the most common being cyclophosphamide, doxorubicin and 5-fluorouracil.
Sustained or controlled release of chemotherapeutic drugs directly into wounds after the removal of high grade malignancies may provide control of microscopic residual cancer cells and avoid system toxicity and wound healing problems while allowing early ablative surgery with the preservation of function of the formerly diseased area. To this end, the controlled delivery of bioactive agents from polymeric materials has attracted considerable attention of investigators throughout the scientific community for more than two decades. The trend in drug delivery technology has been toward bioresorbable polymer excipients requiring no follow-up surgical removal once the drag supply is depleted. Such polymers offer the great advantage of enabling either site-specific or systemic administration of pharmaceutical agents.
Specifically, bioresorbable polymer technologies have been developed for targeted and controlled drug delivery of chemotherapeutic drugs to treat cancer. Most of these polymer delivery systems are based on gel, nanoparticals or microsphere technology for administration via intravenous injection. Others are solid or architecturally ill-defined polymer wafers and blocks that require surgical implantation. The devices of U.S. Pat. Nos. 5,855,608; 5,981,825; and 6,264,701, each of which are incorporated herein by reference and hereinafter referenced to as the OPLA matrix, have proven to produce tissue engineering constructs capable of directing the formation of single or multiple functional tissues in bone, cartilage and soft tissue applications. Study has occurred in the canine osteosarcoma model of the use of the OPLA matrix joined to Cis-diamminedichloroplatinum H (CDDP; cisplatin; Platinol™, hereinafter cisplatin). Cisplatin is a heavy metal complex agent that has been used for many years in chemotherapy protocols. The resulting chemotherapy delivery system provided initially high local concentrations followed by a lower but sustained systemic delivery of cisplatin at therapeutic doses and showed efficacy from the standpoint of local primary tumor control and control of occult metastatic disease. Specifically, the chemotherapy delivery system consisted of a porous body implant defined by an internal architecture of partially enclosed, randomly sized, shaped and positioned intercommunicating interstices. The cisplatin is joined to the polymer during manufacturing yielding 8% cisplatin by weight of total polymer. Sterilization is achieved by exposure of the finished chemotherapy delivery system to 2.5 Mrads of gamma irradiation. The hypothesis of the chemotherapy delivery system is that a low but sustained therapeutic dose of cisplatin will decrease system toxicity while delaying or preventing distant metastasis.
Pharmacokinetic and local/systemic effect studies conducted on the chemotherapy delivery system device documented that except for some mild, self-limiting swelling and edema of soft tissue at the surgery site, no overt systemic or local clinical toxicity was detected with the chemotherapy delivery system. The usual maximum dose-limiting schedule for cisplatin given intravenously to dogs is 70 mg/m2. The dose with the chemotherapy delivery system exceeded the maximum dose-limitation by approximately 16.5% without clinically detectable systemic toxicity. The peak serum dose of platinum from the chemotherapy delivery system was 20% of that seen with a similar intravenous dose. The area under the curve for total serum platinum concentration with the chemotherapy delivery system was shown to be 27 times that of a similar dose of intravenous platinum. Toxicity to bone marrow, kidney, nervous tissue or any other organ was negligible and the chemotherapy delivery system provided higher total sustained levels of the drug with less systemic toxicity than can be achieved by intermittent intravenous administration.
Thus, a need continues to exist for devices and methods for delivering cytotoxic agents which overcome the shortcomings and deficiencies of the prior art.